NR4A2

Gene Facts

• HGNC Symbol: NR4A2 (HGNC:7981)
• HGNC Name: nuclear receptor subfamily 4 group A member 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: NURR1
• Alias symbols: TINUR, NOT, RNR1, HZF-3
• %HI: 1.28
• pLI: 1
• LOEUF: 0.09
• Cytoband: 2q22-q23
• Genomic Coordinates:

  GRCh37/hg19:	chr2:157180949-157189233
  GRCh38/hg38:	chr2:156324437-156332721

• MANE Select Transcript: NM_006186.4 ENST00000339562.9
• Function: Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development (PubMed:17184956, PubMed:15716272). It is crucial for expression of a set of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons (By similarity). {ECO:0000250|UniProtKB:Q06219, ECO:0000269|PubMed:15716272, ECO:0000269|PubMed:17184956}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-25535
• ClinGen Curation ID: CCID:007575
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 09/27/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Complex Neurodevelopmental Disorder

HI Evidence

• PUBMED: 28544326
  Reuter et al. 2017 described a female with mild intellectual disability and speech and language impairment. CMA testing detected a 89 kb de novo deletion of 2q24.1 with included only the gene NR4A2. A second small deletion at 1p36.33 was also detected but was inherited from the healthy mother.
• PUBMED: 29770430
  Levy et al. 2018 reported two patients with focal deletions of NR4A2. The first patient had mild to moderate intellectual disability and autism spectrum disorder. Patient 2 had global developmental delay and language deficits. Both patients were found to have de novo deletions of NR4A2 by CMA.
• PUBMED: 31428396
  Ramos et al. 2019 reported a de novo frameshift variant in NR4A2 (p.Ser110Valfs*2) in a patient with epilepsy, language impairment and intellectual disability.
• PUBMED: 32366965
  Singh et al. 2020 reported three patients with likely loss-of-functions variants in NR4A2. All three patients had global developmental delay, speech and language impairment, and hypotonia. Two patients also had seizures. Two variants (c.865-1_865delGCinsAAAAAGGAGT and p.Q109Pfs*3) were confirmed de novo. A nonsense variant (p.E526*) was not detected in the mother but the father was unavailable for testing.
• PUBMED: 31922365
  Wirth et al. 2020 reported loss of function variants in two patients with mild intellectual disability who developed dystonia parkinsonism in early adulthood. Patient one had a history of mild intellectual disability with prominent language impairment in childhood. He developed seizures and paroxysmal episodes of generalized dystonia in early adulthood. This patient carried the same NR4A2 p.Ser110Valfs*2 variant reported in Ramos et al 2019. The variant was not present in the asymptomatic parents, brother, and sister. Patient 2 had a history of mild intellectual disability. At age 30 she developed tremors and progressed to an early-onset dystonia parkinsonism syndrome. A frameshift variant in NR4A2 (p.Asn294fs) was identified, however, inheritance could not be assessed. The authors suggest dystonia may be a later onset symptom in patients with NR4A2 pathogenic variants.
• PUBMED: 30504930
  Guo, et al. (2019) used genome sequencing on 180 families with autism spectrum disorder. One participant was identified to have a de novo frameshift variant in NR4A2.

• HI Evidence Comments: Deletion or loss of function variants in NR4A2 have been reported in multiple individuals with mild to moderate intellectual disability and language impairment. Other phenotypes may include seizures and early adult onset dystonia. Additional references: PMID: 35992907 Using exome sequencing, Song et al (2022) detected a splice site variant (c.1541-2A>C) and a nonsense variant (p.Cys305*) in NR4A2 in two individuals with developmental delay, speech impairment, and ADHD. Both variants were de novo. PMID: 35813072 Krgovic et al (2022) detected one truncating variant (p.Gln191*) in NR4A2 by exome sequencing in a cohort of 147 children with autism spectrum disorder. The variant was not present in either parent.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity